Presenilin-dependent gamma-secretase-mediated control of p53-associated cell death in Alzheimer's disease.
J Neurosci
; 26(23): 6377-85, 2006 Jun 07.
Article
em En
| MEDLINE
| ID: mdl-16763046
ABSTRACT
Presenilins (PSs) are part of the gamma-secretase complex that produces the amyloid beta-peptide (Abeta) from its precursor [beta-amyloid precursor protein (betaAPP)]. Mutations in PS that cause familial Alzheimer's disease (FAD) increase Abeta production and trigger p53-dependent cell death. We demonstrate that PS deficiency, catalytically inactive PS mutants, gamma-secretase inhibitors, and betaAPP or amyloid precursor protein-like protein 2 (APLP2) depletion all reduce the expression and activity of p53 and lower the transactivation of its promoter and mRNA expression. p53 expression also is diminished in the brains of PS- or betaAPP-deficient mice. The gamma- and epsilon-secretase-derived amyloid intracellular C-terminal domain (AICD) fragments (AICDC59 and AICDC50, respectively) of betaAPP trigger p53-dependent cell death and increase p53 activity and mRNA. Finally, PS1 mutations enhance p53 activity in human embryonic kidney 293 cells and p53 expression in FAD-affected brains. Thus our study shows that AICDs control p53 at a transcriptional level, in vitro and in vivo, and that FAD mutations increase p53 expression and activity in cells and human brains.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Endopeptidases
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Proteína Supressora de Tumor p53
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Doença de Alzheimer
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Proteínas de Membrana
Tipo de estudo:
Observational_studies
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Risk_factors_studies
Idioma:
En
Ano de publicação:
2006
Tipo de documento:
Article